This study examined how controlled punch surface preparation and subsequent atmospheric aging influence adhesion between punch metal and formulation powder during tablet compaction. We aimed to clarify how the evolving surface state of S7 tool steel affects sticking for representative excipients and active pharmaceutical ingredients (APIs), and to establish a reproducible approach for surface state control in material-sparing sticking studies. Removable S7 tool steel punch tips were mechanically polished, chemically cleaned, and rinsed to create a defined “as-cleaned” surface. Punches were aged at 55

Most challenges during the development of solid dosage forms are related to the impact of any variations in raw material properties, batch size, or equipment scales on the product quality and the control of the manufacturing process. With the ever pertinent restrictions on time and resource availability versus heightened expectations to develop, optimize, and troubleshoot manufacturing processes, targeted and robust science-based process modeling platforms are essential. This review focuses on the modeling of unit operations and practices involved in batch manufacturing of solid dosage forms by direct compaction. An effort is made to highlight the key advances in the past five years, and to propose potentially beneficial future study directions.

The bulk properties of a powder are dependent on the preparation, treatment, and storage of the sample, that is, how it was handled. The particles can be packed to have a range of bulk densities and, moreover, the slightest disturbance of the powder bed may result in a changed bulk density. Thus, the bulk density of a powder is often difficult to measure with good reproducibility and, in reporting the results, it is essential to specify how the determination was made. In this article, we measured the bulk density, tapped density, and calculated the Hausner ratio of commonly used excipients with similar tapped density testers and followed the United States Pharmacopeia 30-National Formulary 25-S1 testing procedure. Based on the analysis, within lot and lot-to-lot variability and the relative errors for bulk density, tapped density, and Hausner ratio were found to be acceptable. Lot-to-lot differences were generally not measurable using this test as they were found to be within the variability of the test. The results also indicated that there was no statistically significant bias between sites for tapped density and Hausner ratio, but there was a marginally significant bias in the bulk density data set.

The mechanical behavior of powders during die compaction was investigated using the discrete element method (DEM), in which powders are modeled as discrete particles with elastoplastic material behavior. A new adhesive elastoplastic contact model that describes the force displacement behavior of contacting particles subjected to high confining conditions was introduced and implemented in DEM simulations of die compaction and uniaxial tension. The objectives of these simulations were: (1) to investigate the micromechanical behaviors of powder systems during die compaction; (2) to understand the influence of model parameters on the macroscopic behavior; and (3) to develop a methodology for the calibration of the model parameters from macroscopic experimental results. The methodology developed for the calibration of the model parameters was carried out by a combination of statistical design of experiments (DOE) and optimization techniques. The calibration methodology provided simulation results that were in good agreement with experimental results conducted on hot melt extruded (HME) copovidone powder. One of the key advantages of the calibration procedure is the need for only two experimental techniques – die compaction, and diametric compression strength tests. Furthermore, examination of the microscale behavior from simulated results revealed a connection between the level of interparticle cohesion and the corresponding level of residual wall stress of powder compacts after complete unloading in die compaction. It was found that lower levels of interparticle cohesion resulted in decreased residual wall stresses and an increase in the axial spring back from the minimum compact height at the end of compaction. These results suggest that the decrease in residual wall stress and the increase in axial spring back with lower levels of interparticle cohesion depend not only on the elastic properties of the constituent particles during unloading, but also depend on the decohesion of particle-particle contacts.

Amorphous solid dispersions (ASDs) consisting of acetaminophen (APAP) and copovidone were systematically studied to identify effects of drug loading and moisture content on mechanical properties, thermal properties, and tableting behavior. ASDs containing APAP at different levels were prepared by film casting and characterized by differential scanning calorimetry and nanoindentation. The glass transition temperature (Tg) continuously decreased with increasing amount of APAP, but the hardness of ASDs was increased at a low APAP content and reduced at high APAP content. This in turn significantly influenced tablet quality. Water reduced both the hardness and Tg of ASDs, and the APAP loading level corresponding to the transition to the softening mechanism was lower at a higher relative humidity. Overall, the mechanical properties, rather than the thermal properties, better represent the plasticization/antiplasticization effect of small molecule to ASDs.

To obtain quantitative information and mechanistic insight into the problem of sticking of acetylsalicylic acid tablets on a metallic punch.

A risk- and science-based approach to control the quality in pharmaceutical manufacturing includes a full understanding of how product attributes and process parameters relate to product performance through a proactive approach in formulation and process development. For dry manufacturing, where moisture content is not directly manipulated within the process, the variability in moisture of the incoming raw materials can impact both the processability and drug product quality attributes. A statistical approach is developed using individual raw material historical lots as a basis for the calculation of tolerance intervals for drug product moisture content so that risks associated with excursions in moisture content can be mitigated. The proposed method is based on a model-independent approach that uses available data to estimate parameters of interest that describe the population of blend moisture content values and which do not require knowledge of the individual blend moisture content values. Another advantage of the proposed tolerance intervals is that, it does not require the use of tabulated values for tolerance factors. This facilitates the implementation on any spreadsheet program like Microsoft Excel. A computational example is used to demonstrate the proposed method.

This study investigates the relationship between particle interactions dominated by the cohesive van der Waals force and powder flowability for materials commonly used by the pharmaceutical industry in oral solid dosage formulation. This study first sought to correlate the granular Bond number, defined as the ratio of the inter-particle cohesion force to particle weight, to the flow function coefficient, a metric commonly used to assess powder flowability. However, the granular Bond number which strictly quantifies inter-particle cohesiveness was found to correlate poorly with powder flowability due to the complexity associated with particle assemblies. To account for the multitude of interactions between particles of different sizes within a powder and to more precisely predict bulk powder behavior, a population-dependent granular Bond number was proposed. The population-dependent granular Bond number which explicitly accounts for particle size distribution and described herein as a quantification of powder cohesiveness (instead of inter-particle cohesiveness) was shown to correlate well with the flow function coefficient for a wide variety of materials including four active pharmaceutical ingredients (APIs) and fourteen common pharmaceutical excipients. Due to the success of the population-dependent granular Bond number, it was extended to predict the flowability of powder blends. This so-called population-dependent multi-component granular Bond number takes into account relevant material properties and particle interactions and was used to predict the flowability of 6-component powder blends containing acetaminophen as a model cohesive active pharmaceutical ingredient. Prediction of bulk powder behavior from individual material properties as accomplished here may be highly useful in formulation development.

A finite element study of the interparticle force–displacement laws on contacts of spheres at conditions corresponding to compacts pressed to high relative densities is presented here. Under these conditions, the response of a contact can be affected by the presence of neighboring contacts. Finite element simulations of axisymmetric models of equispaced and equally loaded contacts show that the force–displacement law is not unique and depends on the number of neighboring contacts. The force at a given interparticle deformation is minimum for Z=2 but at higher coordination numbers becomes larger after a critical deformation due to the interaction of the stress fields of neighboring contacts. This difference is magnified when the local porosity closes. Furthermore, numerical simulations of periodic arrays of spheres were conducted to assess the effect of loading path and the formation of new contacts on the response of existing contacts. In both cases, it was found that, the contact response depends on the overall triaxiality of the deformation of the particle. A new deformation fabric tensor is proposed based on the deformation and direction of all contacts on a particle. The first and second invariants of this tensor are used to characterize the triaxiality of the deformation on a particle. These results form the basis for more appropriate force–displacement laws at contacts that can be implemented in discrete element simulations for high density problems.

In order to improve fundamental understanding of powder flow behavior which is essential to the success of many pharmaceutical processes, this study investigates the relationship between particle-scale interactions dominated by the cohesive van der Waals force and the flow function coefficient. This study finds that the granular Bond number, defined as the ratio of the inter-particle cohesion force to particle weight, correlates well to the flow function coefficient, a metric used to assess powder flow performance and defined as the ratio of consolidation stress to unconfined yield strength. The inter-particle cohesion force was calculated by the so-called multi-asperity model which is a modification of the well-known Rumpf equation. As a major novelty, a granular Bond number is defined for multi-component mixtures (i.e. powder blends) and used to predict the flow function coefficient of binary, ternary, and quinary mixtures of a model API, acetaminophen, and two common pharmaceutical excipients, microcrystalline cellulose and pregelatinized starch. Surface modification via dry-coating was also used to alter the inter-particle force and more thoroughly investigate the effect of particle interactions on powder flow performance. Since the multi-component granular Bond number takes into account particle properties and particle interactions of all components in the powder blend, this novel approach shows good predictability for powder mixtures. Although the flow function coefficient alone is not a stringent prediction of powder flow, the modeling effort put forth in this study can be used to better guide formulation development.

The present study explores new approaches to extract Drucker–Prager/Cap (DPC) constitutive model parameters at low and high densities of compacted powders for which it is not possible to get solid, undamaged samples for model calibration purposes. Extrapolations were carried out by invoking a number of physically plausible assumptions for high density conditions and the addition of the experimental shear cell testing procedure for low density extrapolations. The effects of these extrapolations on finite element model (FEM) results of both die compaction and roller compaction were examined. The sensitivity of the extrapolated DPC parameters on compaction model results was explored by performing parametric studies for both low and high density extrapolations. Examination of die compaction model results for low density showed little sensitivity to extrapolations; however, we are able to show that extrapolations of DPC parameters to low density may have a significant effect on roller compaction modeling results. High density die compaction FEM simulations reveal a significant effect on the way in which the DPC model parameters are extrapolated to high density. A method of extrapolating the DPC model parameters to high density is presented in this work. The work presented here demonstrates the significance of properly calibrating the DPC model at low and high densities and provides the necessary guidance for this purpose.

In an effort to identify the origin and the evolution of damage during the compaction/ejection cycle of powder compacts, an experimental study that compares compacts in straight and tapered dies in terms of the presence and growth of microcracks was carried out using x-ray tomography and environmental scanning electron microscopy. The results presented here document the presence of internal microcracks at high relative densities, and microcracks on the surface of the compacts. Parts compacted in tapered dies exhibit microcracks with smaller crack tip opening and have a higher axial strength than those made in a straight die. These experimental observations, together with the ideas of damage generation under compressive stresses, as well as finite element analysis of the stress field in the compact as it exits from the die, confirm the hypothesis that a two-step mechanism is responsible for damage generation in powder compacts. First, microcracking occurs during unloading within the die at high pressures and subsequently surface cracks grow under the localized stresses as the compact emerges from the die.

Drying is one of the most commonly used unit operations in the preparation of dry granules by thermally removing volatile solvent from the wet solid. The study focuses on the quantitative investigation of heat transfer in a filter dryer in the quest to determine the optimum drying conditions. Consequently, contact drying kinetics of glassbeads–ethanol and lactose–ethanol system is investigated using an agitated filter dryer (Charles Thompson). Discrete element method is employed to simulate granular flow, mixing and heat transport in the vessel. Typical system with glass beads is numerically simulated using appropriate material properties and validated by the experimental findings. A parametric study for both simulations and experiments is performed to assess the effect of various conditions of wall temperature, fill level and impeller speed on the drying performance in the filter dryer. A high wall temperature showed an increase in the drying rate and a sharp rise in the average bed temperature, thereby decreasing the total time for drying operation. An increase in fill volume (bed depth) at constant wall temperature and speed resulted in a decline in the drying rate. The rotational speed had a nominal impact on drying of glass beads. Hence low rotational speeds seemed optimal for contact drying.

Process control of aqueous tablet coating depends on a number of thermodynamic and psychrometric variables. Since many of these variables are interdependent, the choice of parameters by which to control the process or designate a design space is not necessarily obvious. Several mass or heat conservation models for aqueous tablet coating can be found in the literature, varying in approach and proposed method for controlling the coating process. A commonly used first-principles model built upon the coupled heat and mass transfer in evaporative mass transfer derives an “Environmental Equivalency” (EE) factor as an indicator of the relative rate of water evaporation from the tablet bed surface and as a relevant scaling factor for aqueous coating. The EE factor is expressed by an equation involving ten individual parameters; however, if the derivation of EE is extended further under the context of an adiabatic process, a much-simplified yet equivalent expression for EE emerges consisting of only three parameters, each directly measurable or obtainable from a psychrometric chart and which bear direct significance to the gross thermodynamic conditions of the coating. The psychrometric model herein is presented as a more physically evocative description of the coating process, enhancing process understanding and potentially playing a key role in a Quality by Design approach to defining an aqueous coating design space.

Publisher Summary A manufacturing process may be scaled by extensive experimentation without any theoretical linkage, to connect that knowledge together to form real process understanding. The efficient scale-up of a pharmaceutical process depends upon a significant understanding of the behavior of the system(s) in question, which in turn relies upon the formation of models that are sophisticated enough to capture the relevant processes and parameters, yet simple enough to be tractable, and this in turn requires at least some a priori knowledge of what physical phenomena may be important to the system behavior, and what may be tentatively ignored. Dimensional analysis is a method used to identify dimensionless numbers that describe how the behavior of a scaled-down prototype can be interpreted, so that it is predictive of the full-sized process intended to model. Scale-up is most easily achieved by keeping these dimensionless numbers constant when changing scale. The mechanistic modeling can produce models that generate predictions that are accurate over a greater range of operating conditions than dimensional analysis models that tend to scale-up any experimental error along with the intended process parameters. It is an ideal tool for the study of specific parameters involved with the phenomena being modeled, since the mechanistic model affords the investigator the opportunity to independently alter any one parameter to study its effects on the model output.